Despite the fact that lead poisoning is a significant human health problem affecting almost one in twenty young children in the US, the mechanism of lead poisoning is not understood at the molecular level. Recent advances in neurobiology and human genetics have pinpointed two metalloproteins that are likely targets for lead in vivo: synaptotagmin (Syt), a calcium metalloprotein, and delta-aminolevulinic acid dehydratase (ALAD), a zinc metalloprotein. The goal of the proposed research is to advance out molecular understanding of lead toxicity and support active field of structural and spectroscopic investigations via a computational modeling of structural effects caused by lead substitution in zinc metalloproteins. Specifically, the aims of this study are (1) to determine and provide a molecular understanding of structural and spectral effects of lead's distinct preferences for highly asymmetrical tetra-coordinated structures, believed to be caused by a stable, inert outer lone pair of electrons, when it binds to typical structural zinc sites of metalloproteins, (2) to provide a molecular interpretation of Pb-cysteine charge-transfer bands and pinpoint its significance to reveal mechanisms of lead toxicity via resonance Raman spectroscopy when intertwined with theoretical predictions. By investigating lead's interactions and effects on typical structural zinc sites of metalloproteins and numerous model compounds we seek to gain a broad understanding of the mechanisms of lead toxicity. Furthermore, the studies proposed herein will provide the foundation for future studies by providing accurate and reliable methodologies for computational investigations of other heavy metal poisoning by such elements as mercury, cadmium and arsenic.